KR20010101699A - Potassium Salt of (S)-Omeprazole - Google Patents
Potassium Salt of (S)-Omeprazole Download PDFInfo
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- KR20010101699A KR20010101699A KR1020017009374A KR20017009374A KR20010101699A KR 20010101699 A KR20010101699 A KR 20010101699A KR 1020017009374 A KR1020017009374 A KR 1020017009374A KR 20017009374 A KR20017009374 A KR 20017009374A KR 20010101699 A KR20010101699 A KR 20010101699A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/33—Heterocyclic compounds
- A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
- A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
- A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
- A61K31/4427—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems
- A61K31/4439—Non condensed pyridines; Hydrogenated derivatives thereof containing further heterocyclic ring systems containing a five-membered ring with nitrogen as a ring hetero atom, e.g. omeprazole
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
- A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
Abstract
본 발명은 일반명 오메프라졸로 공지된 5-메톡시-2-[[(4-메톡시-3,5-디메틸-2-피리디닐)메틸]술피닐]-1H-벤즈이미다졸의 신규 형태에 관한 것이다. 보다 구체적으로는, 5-메톡시-2-[[(4-메톡시-3,5-디메틸-2-피리디닐)메틸]술피닐]-1H-벤즈이미다졸의 (S)-에난티오머의 칼륨염의 신규 결정형에 관한 것이다. 본 발명은 또한 상기한 형태의 (S)-오메프라졸의 칼륨염의 제조 방법 및 이를 함유하는 제약 조성물에 관한 것이다.The present invention is a novel form of 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl) methyl] sulfinyl] -1 H -benzimidazole known under the common name omeprazole. It is about. More specifically, (S) -enantio of 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl) methyl] sulfinyl] -1 H -benzimidazole It relates to a new crystalline form of the potassium salt of mer. The present invention also relates to a process for the preparation of the potassium salt of (S) -omeprazole of the above form and to pharmaceutical compositions containing the same.
Description
일반명이 오메프라졸인 화합물 5-메톡시-2-[[(4-메톡시-3,5-디메틸-2-피리디닐)메틸]술피닐]-1H-벤즈이미다졸 및 그의 치료학상 허용되는 염이 EP 5129호에 기재되어 있다. 오메프라졸의 특정 알칼리성 염들은 EP 124 495호에 개시되어 있다. 오메프라졸은 프로톤 펌프 억제제, 즉 위산 분비를 억제하는데 효과적이고, 항궤양제로서 유용하다. 보다 일반적인 의미에서, 오메프라졸은 포유동물, 특히 사람의 위산 관련 질병의 예방 및 치료에 사용될 수 있다.Compound 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl) methyl] sulfinyl] -1 H -benzimidazole and its therapeutically acceptable salts having the common name omeprazole This is described in EP 5129. Particular alkaline salts of omeprazole are disclosed in EP 124 495. Omeprazole is effective in inhibiting proton pump inhibitors, ie gastric acid secretion, and is useful as an antiulcer agent. In a more general sense, omeprazole can be used for the prevention and treatment of gastric acid related diseases in mammals, especially humans.
오메프라졸은 술폭시드로서, 황 원자가 입체 중심인 키랄 화합물이다. 따라서, 오메프라졸은 그의 2종의 단일 에난티오머들, 오메프라졸의 (R) 및 (S)-에난티오머 (본 명세서에서는 (R)-오메프라졸 및 (S)-오메프라졸로 언급됨)의 라세미 혼합물이다. 오메프라졸의 에난티오머들의 절대적 배위는 비염 형태의 (+)-에난티오머의 N-알킬화 유도체의 X선 연구에 의해 결정되어 있다. 비염 형태의 (+)-에난티오머 및 비염 형태의 (-)-에난티오머는 각각 R 및 S 배위를 갖는 것으로 밝혀졌다. 이들 에난티오머 각각에 대한 광회전 측정을 위한 조건들은 WO 94/27988호에 기재되어 있다.Omeprazole is a sulfoxide, a chiral compound whose sulfur atom is a stereogenic center. Thus, omeprazole is a racemic mixture of its two single enantiomers, (R) and (S) -enantiomers of omeprazole, referred to herein as (R) -omeprazole and (S) -omeprazole. to be. The absolute coordination of enantiomers of omeprazole is determined by X-ray studies of N-alkylated derivatives of the (+)-enantiomers in the non-salt form. The non-salt form of (+)-enantiomers and the non-salt form of (-)-enantiomers are R and S, respectively. It was found to have coordination. Conditions for measuring optical rotation for each of these enantiomers are described in WO 94/27988.
오메프라졸의 단일 에난티오머들의 특정 염 및 이들의 제법이 WO 94/27988호에 개시되어 있다. 이들 화합물은 개별 변화 정도가 보다 낮은 것과 같은 개선된 치료 프로필을 제공하게 되는 개선된 약물동력학적 및 대사적 특성들을 갖는다.Certain salts of single enantiomers of omeprazole and their preparation are disclosed in WO 94/27988. These compounds have improved pharmacokinetic and metabolic properties that will provide an improved therapeutic profile, such as a lower degree of individual change.
WO 96/02535호는 오메프라졸의 단일 에난티오머 및 구조상 관련된 화합물 뿐만 아니라 그의 염의 제조 방법을 개시하고 있다. WO 96/01623호는 예를 들면 (R) 및 (S)-오메프라졸의 마그네슘염을 포함하는 제약 투여 형태를 개시한다.WO 96/02535 discloses the preparation of single enantiomers and structurally related compounds of omeprazole as well as their salts. WO 96/01623 discloses pharmaceutical dosage forms comprising, for example, magnesium salts of (R) and (S) -omeprazole.
WO 98/54171호는 (S)-오메프라졸의 칼륨염을 중간체로 사용하는, (S)-오메프라졸의 마그네슘의 삼수화물의 제조 방법을 개시하고 있다. 선행 기술에 따라 (S)-오메프라졸의 칼륨염은 메탄올 용매화물로서 결정화된다.WO 98/54171 discloses a process for the preparation of magnesium trihydrate of (S) -omeprazole, using the potassium salt of (S) -omeprazole as an intermediate. According to the prior art the potassium salt of (S) -omeprazole is crystallized as methanol solvate.
(S)-오메프라졸의 칼륨염과 같은 특정 염은 물에서의 고 안정성 및 고 용해성과 같은 고유한 특정으로 인해 일반적으로 정맥내 투여에 적합한 화합물이다. 그러나 메탄올과 함께 투여하는 것은 수용자에게 치명적일 수 있기 때문에 메탄올 용매화물은 정맥내 투여에 적합하지 않다. 그러므로, 메탄올이 없는 (S)-오메프라졸의 칼륨염이 필요로 된다.Certain salts, such as the potassium salt of (S) -omeprazole, are generally compounds suitable for intravenous administration due to their inherent properties such as high stability and high solubility in water. However, methanol solvates are not suitable for intravenous administration because administration with methanol can be fatal to the recipient. Therefore, potassium salt of (S) -omeprazole without methanol is needed.
본 발명에 따라 (S)-오메프라졸의 칼륨염의 신규형은 이후 (S)-오메프라졸칼륨염의 형태 B라 한다. WO 98/54171호에 개시된 (S)-오메프라졸의 칼륨염의 선행 기술 형태는 이후 (S)-오메프라졸 칼륨염의 형태 A라 한다.According to the invention a novel form of the potassium salt of (S) -omeprazole is hereafter referred to as Form B of the (S) -omeprazole potassium salt. The prior art form of the potassium salt of (S) -omeprazole disclosed in WO 98/54171 is hereafter referred to as Form A of (S) -omeprazole potassium salt.
본 발명은 일반명 오메프라졸로 공지된 5-메톡시-2-[[(4-메톡시-3,5-디메틸-2-피리디닐)메틸]술피닐]-1H-벤즈이미다졸의 신규 형태에 관한 것이다. 보다 구체적으로는, 5-메톡시-2-[[(4-메톡시-3,5-디메틸-2-피리디닐)메틸]술피닐]-1H-벤즈이미다졸의 (S)-에난티오머의 칼륨염의 신규 결정형에 관한 것이다. 본 발명은 또한 상기한 형태의 (S)-오메프라졸의 칼륨염의 제조 방법 및 이를 함유하는 제약 조성물에 관한 것이다.The present invention is a novel form of 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl) methyl] sulfinyl] -1 H -benzimidazole known under the common name omeprazole. It is about. More specifically, (S) -enantio of 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl) methyl] sulfinyl] -1 H -benzimidazole It relates to a new crystalline form of the potassium salt of mer. The present invention also relates to a process for the preparation of the potassium salt of (S) -omeprazole of the above form and to pharmaceutical compositions containing the same.
도 1은 본 발명에 따라 제조된 (S)-오메프라졸 칼륨염, 즉 형태 B의 X선 분말 회절도를 나타낸다.1 shows an X-ray powder diffractogram of (S) -omeprazole potassium salt, ie Form B, prepared according to the present invention.
도 2는 WO 98/54171호의 실시예 2에 따라 제조된 (S)-오메프라졸의 칼륨염, 즉 형태 A의 X선 분말 회절도를 나타낸다.2 shows the X-ray powder diffractogram of the potassium salt of (S) -omeprazole, ie Form A, prepared according to Example 2 of WO 98/54171.
놀랍게도, 본 발명자들은 (S)-오메프라졸의 칼륨염이 많은 구조적으로 상이한 형태들로 발생된다는 것을 밝혀내었다. 본 발명의 목적은 실질적으로 순수한 (S)-오메프라졸 칼륨염의 형태 B를 제공하는 것이다.Surprisingly, the inventors have found that the potassium salt of (S) -omeprazole occurs in many structurally different forms. It is an object of the present invention to provide Form B of substantially pure (S) -omeprazole potassium salt.
이전에 공지된 형태 A가 메탄올 용매화물인데 반해 (S)-오메프라졸 칼륨염의 형태 B는 수화물 형태이므로 이롭다. (S)-오메프라졸 칼륨염의 형태 B는 정맥내 투여에 특별히 적합하다. (S)-오메프라졸 칼륨염의 형태 B는 또한 결정성, 바람직하게는 고결정성을 특징으로 한다.Form A of the (S) -omeprazole potassium salt is advantageous because it is in the form of a hydrate, whereas previously known form A is a methanol solvate. Form B of (S) -omeprazole potassium salt is particularly suitable for intravenous administration. Form B of (S) -omeprazole potassium salt is also characterized by crystalline, preferably high crystallinity.
본 발명에 따라 얻어진 (S)-오메프라졸 칼륨염의 형태 B는 실질적으로 (S)-오메프라졸 칼륨염의 다른 형태, 예컨대 선행 기술에 기재된 상응하는 형태 A를 함유하지 않는다. 본 발명에 따라 얻어진 (S)-오메프라졸 칼륨염의 형태 B는 또한 실질적으로 (R)-오메프라졸 칼륨염을 함유하지 않는다.Form B of (S) -omeprazole potassium salt obtained according to the present invention is substantially free of other forms of (S) -omeprazole potassium salt, such as the corresponding form A described in the prior art. Form B of the (S) -omeprazole potassium salt obtained according to the present invention is also substantially free of the (R) -omeprazole potassium salt.
(S)-오메프라졸 칼륨염의 형태 B는 X선 분말 회절도의 주요 피크의 위치 및강도에 의해 특성화되지만, 종래의 FT-IR 분광분석법에 의해서도 특성화될 수 있다. 이들 특성들은 (S)-오메프라졸 칼륨염의 임의의 다른 형태에 의해서는 나타나지 않으며, 따라서 (S)-오메프라졸 칼륨염의 형태 B는 선행 기술에서 개시된 임의의 다른 (S)-오메프라졸 칼륨염의 결정 형태와 용이하게 구별될 수 있다. 표현 "임의의 형태"란, 무수물, 수화물, 용매화물, 무정형 및 다형태를 의미한다. (S)-오메프라졸 칼륨염의 임의의 형태의 예로는 무수물, 일수화물, 이수화물, 1.5수화물, 삼수화물, 알콜레이트, 예컨대 메탄올레이트 및 에탄올레이트, 무정형 및 다형태를 들 수 있지만, 이에 제한되지는 않는다.Form B of (S) -omeprazole potassium salt is characterized by the position and intensity of the main peak of the X-ray powder diffractogram, but can also be characterized by conventional FT-IR spectroscopy. These properties are not exhibited by any other form of (S) -omeprazole potassium salt, so Form B of (S) -omeprazole potassium salt is readily available with the crystalline form of any other (S) -omeprazole potassium salt disclosed in the prior art. Can be distinguished. The expression “any form” means anhydride, hydrate, solvate, amorphous and polymorphic. Examples of any form of (S) -omeprazole potassium salt include, but are not limited to, anhydrides, monohydrates, dihydrates, 1.5 hydrates, trihydrates, alcoholates such as methanolate and ethanolate, amorphous and polymorphic. Do not.
(S)-오메프라졸 칼륨염의 형태 B는 그의 단위격자에 의해서도 특성화될 수 있다.Form B of (S) -omeprazole potassium salt can also be characterized by its unit lattice.
추가의 면에서, 본 발명은 (S)-오메프라졸을 톨루엔 또는 디클로로메탄중에서 수산화칼륨 또는 칼륨 메틸레이트와 같은 칼륨 원으로 처리하여 상응하는 칼륨염으로 전환시킨 후, 형성된 염을 단리하는 단계를 포함하는, (S)-오메프라졸 칼륨염의 형태 B의 제조 방법을 제공한다.In a further aspect, the invention comprises treating (S) -omeprazole with a potassium source such as potassium hydroxide or potassium methylate in toluene or dichloromethane to convert to the corresponding potassium salt, and then isolated salts formed. And a process for preparing Form B of (S) -omeprazole potassium salt.
상기 공정에서 사용된 조 (S)-오메프라졸은 예를 들어 5-메톡시-2-[[(4-메톡시-3,5-디메틸-2-피리디닐)메틸]티오]-1H-벤즈이미다졸을 선행 기술 (WO 98/54171호 참조)에 기재된 바와 같이 산화제 및 키랄 티타늄 착물에 의해, 임의로 톨루엔 또는 디클로로메탄과 같은 유기 용매중의 염기의 존재하에 (S)-오메프라졸로 산화시켜 제조할 수 있다.The crude (S) -omeprazole used in the process is, for example, 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl) methyl] thio] -1 H-benzimi Dazoles may be prepared by oxidizing with chiral titanium complexes as described in the prior art (see WO 98/54171) to (S) -omeprazole, optionally in the presence of a base in an organic solvent such as toluene or dichloromethane. have.
본 발명에 따라 제조된 (S)-오메프라졸 칼륨염의 형태 B를 그 자체가 공지되어 있는 기술인 X-선 분말 회절법에 의해 분석하고, 특성화하고, 이전에 공지된 형태 B와 구별한다. (S)-오메프라졸 칼륨염의 형태 B를 분석하고, 특성화하고, 상응하는 형태 A와 구별하는 다른 적합한 기술이 종래의 FT-IR이다.Form B of the (S) -omeprazole potassium salt prepared according to the invention is analyzed, characterized and distinguished from previously known Form B by X-ray powder diffraction which is a technique known per se. Another suitable technique for analyzing, characterizing and distinguishing Form B of (S) -omeprazole potassium salt from the corresponding Form A is conventional FT-IR.
(S)-오메프라졸 칼륨염의 형태 B의 물 함량은 그 자체가 공지되어 있는 기술인 열중량분석법 (TGA)에 의해 결정될 수 있다.The water content of Form B of (S) -omeprazole potassium salt can be determined by thermogravimetric analysis (TGA), a technique by which it is known per se.
(S)-오메프라졸 칼륨염의 형태 B는 위산 분비 억제제로서 효과적이고, 항궤양제로서 유용하다. 보다 일반적인 의미에서, (S)-오메프라졸 칼륨염의 형태 B는 예를 들면, 반추성 식도염, 위염, 십이지장염, 위궤양 및 십이지장궤양을 포함하는, 포유동물, 특히 사람의 위산 관련 질환의 치료에 사용될 수 있다. 또한, (S)-오메프라졸 칼륨염의 형태 B는 위산 억제 효과가 요망되는 다른 위장 장애의 치료를 위하여, 예를 들면 비스테로이드계 소염제 (NSAID) 치료 요법 중의 환자, 비 궤양 소화불량증이 있는 환자, 증후성 위식도 역류성 질환이 있는 환자, 및 가스트리노마 (gastrinomas)가 있는 환자에 사용될 수 있다. (S)-오메프라졸 칼륨염의 형태 B는 또한 중환자실에 있는 환자, 급성 상부 위장관 출혈이 있는 환자에게 위산 흡인의 예방 및 스트레스성 궤양의 치료를 위하여 수술전 및 수술후에 사용될 수 있다. 또한, (S)-오메프라졸 칼륨염의 형태 B는 건선 치료 뿐만 아니라 헬리코박터(Helicobacter) 감염 및 이와 관련된 질환의 치료에 유용할 수 있다. (S)-오메프라졸 칼륨염의 형태 B는 또한 사람을 포함하는 포유동물에서의 염증성 질환의 치료에 사용될 수 있다.Form B of (S) -omeprazole potassium salt is effective as an inhibitor of gastric acid secretion and is useful as an antiulcer agent. In a more general sense, Form B of (S) -omeprazole potassium salt can be used for the treatment of gastric acid related diseases in mammals, especially humans, including, for example, ruminant esophagitis, gastritis, duodenitis, gastric ulcer and duodenal ulcer have. In addition, Form B of (S) -omeprazole potassium salt is useful for the treatment of other gastrointestinal disorders in which gastric acid inhibitory effect is desired, for example, patients in nonsteroidal anti-inflammatory drugs (NSAID) therapy, patients with non-ulcer dyspepsia, symptoms It can be used in patients with gastroesophageal reflux disease, and in patients with gastrinomas. Form B of (S) -omeprazole potassium salt may also be used preoperatively and postoperatively for the prevention of gastric aspiration and for the treatment of stress ulcers in patients in the intensive care unit, patients with acute upper gastrointestinal bleeding. In addition, (S) - omeprazole potassium salt form B may be useful in the H. pylori (Helicobacter) treatment of the infection and associated diseases as well as psoriasis. Form B of (S) -omeprazole potassium salt can also be used for the treatment of inflammatory diseases in mammals, including humans.
환자에게 본 발명에 따른 (S)-오메프라졸 칼륨염의 형태 B의 유효 투여량을제공하기 위하여 적합한 모든 투여 경로를 이용할 수 있다. 예를 들면, 경구 또는 비경구 제형 등이 사용될 수 있다. 투여형으로는 캡슐제, 정제, 분산액, 현탁액 등을 들 수 있다. (S)-오메프라졸 칼륨염의 형태 B은 물에서 높은 수용성을 갖기 때문에 정맥내와 같은 비경구 제형에 특별히 적합하다.Any suitable route of administration can be used to provide the patient with an effective dosage of Form B of the (S) -omeprazole potassium salt according to the invention. For example, oral or parenteral formulations and the like can be used. Dosage forms include capsules, tablets, dispersions, suspensions and the like. Form B of the (S) -omeprazole potassium salt is particularly suitable for parenteral formulations such as intravenous because it has high water solubility in water.
본 발명에 따라 활성 성분으로서 (S)-오메프라졸 칼륨염의 형태 B를 제약학상 허용되는 담체, 희석제 또는 부형제, 및 임의로 다른 치료 성분들과 함께 포함하는 제약 조성물이 추가로 제공된다. 기타 치료 성분들을 포함하는 조성물은 특히 헬리코박터 감염의 치료에 유리하다. 본 발명은 또한 위산 관련 질환의 치료에 사용하기 위한 의약의 제조에 사용되는 (S)-오메프라졸 칼륨염의 형태 B의 용도, 및 상기 질환을 앓는 환자에게 (S)-오메프라졸 칼륨염의 형태 B의 치료학적 유효량을 투여하는 것을 포함하는 위산 관련 질환의 치료 방법을 제공한다.According to the invention there is further provided a pharmaceutical composition comprising Form B of (S) -omeprazole potassium salt as an active ingredient with a pharmaceutically acceptable carrier, diluent or excipient, and optionally other therapeutic ingredients. Compositions comprising other therapeutic ingredients are particularly advantageous for the treatment of Helicobacter infection. The present invention also relates to the use of Form B of (S) -omeprazole potassium salt for use in the manufacture of a medicament for use in the treatment of gastric acid related diseases, and to the patients suffering from the disease, the therapeutic of Form B of (S) -omeprazole potassium salt. Provided are methods of treating gastric acid related diseases comprising administering an effective amount.
본 발명의 조성물에는 경구 또는 비경구 투여에 적합한 조성물이 포함된다. 조성물은 편리하게는 단위 투여형으로 제공될 수 있으며, 제약 분야에 공지되어 있는 임의의 방법에 의해 제조될 수 있다.Compositions of the present invention include compositions suitable for oral or parenteral administration. The compositions may conveniently be presented in unit dosage form and may be prepared by any of the methods known in the art of pharmacy.
본 발명의 실행에서, 임의의 주어진 경우에서 (S)-오메프라졸 칼륨염의 형태 B의 치료학적 투여량 뿐만 아니라 가장 적합한 투여 경로는 치료하고자 하는 질환의 성질 및 심각성에 따라 달라질 것이다. 투여량 및 투여 횟수도 또한 각 환자의 연령, 체중 및 반응에 따라 변할 수 있다. 평균 환자보다 많은 투여량을 필요로 하는 것과 같은 졸링거-엘리슨 증후군이 있는 환자의 경우 특별한 요구조건이 필요할 수 있다. 장기간 치료받는 환자 뿐만 아니라 간 질환이 있는 환자 및 어린이는일반적으로 평균보다 다소 더 적은 투여량이 유리할 것이다. 따라서, 몇몇 경우에서는 아래에서 기술하는 범위 밖의 투여량을 사용할 필요가 있다. 이러한 더 많은 또는 더 적은 투여량은 본 발명의 영역 내에 속한다.In the practice of the present invention, in any given case, the therapeutic dosage of Form B of (S) -omeprazole potassium salt as well as the most suitable route of administration will depend on the nature and severity of the disease to be treated. Dosage and frequency of administration may also vary depending on the age, weight and response of each patient. Special requirements may be required for patients with Solinger-Elison syndrome, such as requiring more than the average patient. Patients with liver disease, as well as patients with long-term treatment, will generally benefit slightly less than average doses. Therefore, in some cases it is necessary to use dosages outside the ranges described below. Such higher or lower dosages fall within the scope of the present invention.
일반적으로, 적합한 투여 형태는 한번의 단일 투여량으로 또는 동등하게 분배된 투여량들로 투여되는, 1일 총 투여량이 5 ㎎ 내지 120 ㎎인 범위의 투여량을 포함할 수 있다. 바람직한 투여량 범위는 5 ㎎ 내지 100 ㎎, 더욱 바람직하게는 10 ㎎ 내지 80 ㎎이다. 적합한 투여량은 경구 투여 뿐만 아니라 정맥내 투여에서 20 ㎎ 내지 40 ㎎이다.In general, suitable dosage forms may include dosages ranging from 5 mg to 120 mg in a single daily dose or in equally divided doses. Preferred dosage ranges are 5 mg to 100 mg, more preferably 10 mg to 80 mg. Suitable dosages are 20 mg to 40 mg in oral as well as intravenous administration.
본 발명의 화합물은 종래의 기술에 따른 제약 담체와의 치밀한 혼합물중에 활성 성분으로서 배합될 수 있다. 특별히 적합한 경구 제형은 전체 내용이 본 명세서에서 참고 문헌으로 인용되어 있는 WO 96/01623호 및 EP 247 983호에 기재되어 있다.The compounds of the present invention may be formulated as active ingredients in a dense mixture with pharmaceutical carriers according to the prior art. Particularly suitable oral formulations are described in WO 96/01623 and EP 247 983, which are hereby incorporated by reference in their entirety.
분리 투여형으로 (S)-오메프라졸 칼륨염의 형태 B 및 다른 활성 성분들을 포함하는 병용 요법도 또한 사용될 수 있다. 상기 활성 성분들의 예로는 항균 화합물, 비스테로이드계 소염제, 제산제, 알긴산염 및 프로카이네틱제 (prokinetic agent)를 들 수 있으나, 이들로 제한되지는 않는다.Combination therapies comprising Form B of the (S) -omeprazole potassium salt and other active ingredients in separate dosage forms can also be used. Examples of the active ingredients include, but are not limited to, antimicrobial compounds, nonsteroidal anti-inflammatory agents, antacids, alginates and prokinetic agents.
하기 실시예는 본 발명의 화합물, 즉 (S)-오메프라졸 칼륨염의 형태 B의 제법을 추가로 예시하나, 상기 정의되거나 또는 하기 청구된 바와 같은 본 발명의 범위를 제한하려는 것은 아니다.The following examples further illustrate the preparation of the compounds of the invention, namely Form B of (S) -omeprazole potassium salt, but are not intended to limit the scope of the invention as defined above or claimed below.
(S)-오메프라졸 칼륨염의 형태 BForm B of (S) -omeprazole potassium salt
톨루엔중의 5-메톡시-2-[[(4-메톡시-3,5-디메틸-2-피리디닐)메틸]티오]-1H-벤즈이미다졸 (67 m㏖)의 용액(5-메톡시-2-[[(4-메톡시-3,5-디메틸-2-피리디닐)메틸]티오]-1H-벤즈이미다졸 1 g당 톨루엔 4 ㎖)을 물 (0.9 m㏖) 및 D-(-)-디에틸 타르트레이트 (14 m㏖)로 50℃에서 충전하였다. 20분 동안 교반한 후, 티타늄 (IV) 이소프로폭시드 (6.5 m㏖)를 가하고, 용액을 약 50분 동안 교반하였다. 반응 혼합물을 35℃로 맞추고, N,N-디이소프로필에틸아민 (10 m㏖)을 가하였다. 그 후, 온도를 약 35℃로 유지시키면서 큐멘 히드로퍼옥시드 (74 m㏖)을 용액에 충전하였다.A solution of 5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl) methyl] thio] -1H-benzimidazole (67 mmol) in toluene (5-methoxy Oxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl) methyl] thio] -1H-benzimidazole 4 ml of toluene per g) of water (0.9 mmol) and D- Charged at 50 ° C. with (−)-diethyl tartrate (14 mmol). After stirring for 20 minutes, titanium (IV) isopropoxide (6.5 mmol) was added and the solution stirred for about 50 minutes. The reaction mixture was adjusted to 35 ° C. and N, N-diisopropylethylamine (10 mmol) was added. The cumene hydroperoxide (74 mmol) was then charged to the solution while maintaining the temperature at about 35 ° C.
3시간 후, 반응 혼합물을 톨루엔 (5-메톡시-2-[[(4-메톡시-3,5-디메틸-2-피리디닐)메틸]티오]-1H-벤즈이미다졸 1 g당 2 ㎖)으로 희석시키고, 칼륨 메톡시드 (26 m㏖)를 톨루엔 (KOMe 1 g당 8 ㎖)중의 슬러리로서 가하였다. 생성된 결정을 여과 분리하고, 밤새 건조시켰다 (36℃, 진공). 수율 0.72 g (1.9 m㏖; KOMe에 대해 7%).After 3 hours, the reaction mixture was added 2 ml per g of toluene (5-methoxy-2-[[(4-methoxy-3,5-dimethyl-2-pyridinyl) methyl] thio] -1 H-benzimidazole ) And potassium methoxide (26 mmol) was added as a slurry in toluene (8 ml per g of KOMe). The resulting crystals were filtered off and dried overnight (36 ° C., vacuum). Yield 0.72 g (1.9 mmol; 7% for KOMe).
칼 피셔 적정 (Karl-Fischer titration) 및 GC로 용매의 함량을 얻었다 (중량/중량%).The content of solvent was obtained by Karl-Fischer titration and GC (weight / weight%).
물 3.4Water 3.4
메탄올 0.01Methanol 0.01
<TGA><TGA>
결정 격자에 혼입된 물 함량은 약 2 중량/중량%이다 (즉, (S)-오메프라졸 칼륨염의 형태 B 분자당 약 0.5 H2O).The water content incorporated in the crystal lattice is about 2% w / w (ie about 0.5 H 2 O per molecule of form B of (S) -omeprazole potassium salt).
<XRD><XRD>
CuKα1로 조사하여 2θ에서 1-40˚로부터 측정된 생성물의 X-선 분말 회절도를 하기 특징 피크 목록에 나타낸다.The X-ray powder diffractogram of the product measured from 1-40 ° at 2θ by irradiation with CuKα 1 is shown in the following feature peak list.
또한, 회절도에 나타난 여러 약한 피크들은 정확도를 위해 생략하였다.Also, several weak peaks shown in the diffractograms are omitted for accuracy.
브래그 (Bragg) 식으로 계산된 d-값으로 확인된 피크 및 강도를 (S)-오메프라졸 칼륨염의 형태 B의 회절도로부터 발췌하였다. 상대 강도는 보다 신뢰성이 부족하여 수치 대신에 하기 정의를 사용한다.Peaks and intensities identified by the d-value calculated by the Bragg equation were extracted from the diffractogram of Form B of (S) -omeprazole potassium salt. Relative strength is less reliable and uses the following definition instead of numerical values.
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| US6489346B1 (en) | 1996-01-04 | 2002-12-03 | The Curators Of The University Of Missouri | Substituted benzimidazole dosage forms and method of using same |
| US5840737A (en) | 1996-01-04 | 1998-11-24 | The Curators Of The University Of Missouri | Omeprazole solution and method for using same |
| US20070060556A1 (en) * | 2003-05-05 | 2007-03-15 | Yatendra Kumar | Barium salt of benzimidazole derivative |
| US8993599B2 (en) | 2003-07-18 | 2015-03-31 | Santarus, Inc. | Pharmaceutical formulations useful for inhibiting acid secretion and methods for making and using them |
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| CN1972928A (en) * | 2004-06-24 | 2007-05-30 | 阿斯利康(瑞典)有限公司 | New process for the preparation of crystal modifications for use in the preparation of esomeprazole sodium salt |
| WO2006073779A1 (en) * | 2004-12-30 | 2006-07-13 | Transform Phamaceuticals, Inc. | Novel omeprazole forms and related methods |
| ES2259269B1 (en) | 2005-03-03 | 2007-11-01 | Esteve Quimica, S.A. | PROCEDURE FOR THE PREPARATION OF DERIVATIVES OF 2- (2-PIRIDILMETILSULFINIL) -BENCIMIDAZOL OPTICALLY ACTIVE. |
| US7576219B2 (en) | 2005-10-26 | 2009-08-18 | Hanmi Pharm. Co., Ltd | Crystalline S-omeprazole strontium hydrate, method for preparing same, and pharmaceutical composition containing same |
| EP1801110A1 (en) | 2005-12-22 | 2007-06-27 | KRKA, tovarna zdravil, d.d., Novo mesto | Esomeprazole arginine salt |
| CN100384839C (en) * | 2006-02-17 | 2008-04-30 | 中国科学院上海有机化学研究所 | Prepn process of [(substituted pyridyl) methyl] sulfenyl-1H-benzimidazole compound and its antimer zinc salt |
| EP2040710A2 (en) * | 2006-06-21 | 2009-04-01 | Glenmark Pharmaceuticals Limited | Novel polymorph of esomeprazole potassium and process for its preparation |
| WO2008067037A2 (en) | 2006-10-05 | 2008-06-05 | Santarus, Inc. | Novel formulations of proton pump inhibitors and methods of using these formulations |
| MX2009004475A (en) | 2006-10-27 | 2009-08-12 | Univ Missouri | Compositions comprising acid labile proton pump inhibiting agents, at least one other pharmaceutically active agent and methods of using same. |
| US7906678B2 (en) | 2006-12-04 | 2011-03-15 | Bayer Schering Pharma Aktiengesellschaft | Crystalline potassium salt of lipoxin A4 analogs |
| FR2920428B1 (en) * | 2007-08-29 | 2012-06-15 | Univ Rouen | PROCESS FOR DEDOLDING SALTS OF OMEPRAZOLE |
| WO2009074997A2 (en) * | 2007-12-10 | 2009-06-18 | Lee Pharma Ltd. | A novel process for the preparation of crystalline magnesium salt of (s)-omeprazole di hydrate |
| EP2143722A1 (en) | 2008-07-09 | 2010-01-13 | Lek Pharmaceuticals D.D. | Process for preparation of esomeprazole sodium of high chemical purity and new forms of esomeprazole sodium |
| WO2010097583A1 (en) | 2009-02-24 | 2010-09-02 | Cipla Limited | Esomeprazole potassium polymorph and its preparation |
| WO2010122583A2 (en) | 2009-04-24 | 2010-10-28 | Rubicon Research Private Limited | Oral pharmaceutical compositions of acid labile substances |
| SI2510089T1 (en) | 2009-12-08 | 2015-12-31 | Codexis, Inc. | Synthesis of prazole compounds |
| CN102319223B (en) * | 2011-09-21 | 2013-06-19 | 石药集团欧意药业有限公司 | Esomeprazole freeze-dried preparation and preparation method thereof |
| CN102633776B (en) * | 2012-03-28 | 2014-06-18 | 中山市仁合药业有限公司 | Method for preparing esomeprazole and sodium salt thereof |
Family Cites Families (14)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| SE7804231L (en) | 1978-04-14 | 1979-10-15 | Haessle Ab | Gastric acid secretion |
| SE8301182D0 (en) | 1983-03-04 | 1983-03-04 | Haessle Ab | NOVEL COMPOUNDS |
| GB2189698A (en) | 1986-04-30 | 1987-11-04 | Haessle Ab | Coated omeprazole tablets |
| DE4035455A1 (en) | 1990-11-08 | 1992-05-14 | Byk Gulden Lomberg Chem Fab | ENANTIOMER SEPARATION |
| US5877192A (en) | 1993-05-28 | 1999-03-02 | Astra Aktiebolag | Method for the treatment of gastric acid-related diseases and production of medication using (-) enantiomer of omeprazole |
| SE9301830D0 (en) | 1993-05-28 | 1993-05-28 | Ab Astra | NEW COMPOUNDS |
| AU695966B2 (en) | 1994-07-08 | 1998-08-27 | Astrazeneca Ab | Multiple unit tableted dosage form I |
| SE504459C2 (en) | 1994-07-15 | 1997-02-17 | Astra Ab | Process for the preparation of substituted sulfoxides |
| GB9423968D0 (en) | 1994-11-28 | 1995-01-11 | Astra Ab | Resolution |
| GB9423970D0 (en) | 1994-11-28 | 1995-01-11 | Astra Ab | Oxidation |
| HRP960232A2 (en) | 1995-07-03 | 1998-02-28 | Astra Ab | A process for the optical purification of compounds |
| SE510666C2 (en) * | 1996-12-20 | 1999-06-14 | Astra Ab | New Crystal Modifications |
| SE510650C2 (en) * | 1997-05-30 | 1999-06-14 | Astra Ab | New association |
| SE510643C2 (en) * | 1997-06-27 | 1999-06-14 | Astra Ab | Thermodynamically stable omeprazole sodium form B |
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